This chapter describes the recently identified molecular, cellular, and brain circuits thought to be responsible for the phenotypic behaviors that characterize mood disorders. It is becoming increasingly clear that the neurochemical and structurally related abnormalities are closely associated with abnormalities in cellular plasticity. The chapter presents preclinical evidence and discusses the data obtained from relevant clinical studies. It provides an overview of the recent neuroimaging findings in mood disorders, highlighting how the extant data implicate a network formed by the medial prefrontal cortex (PFC) and anatomically related areas of the striatum, thalamus, anterior temporal cortex, hippocampus, amygdala, hypothalamus, and brain stem in the pathophysiology of mood disorders. The chapter helps readers make sense of the many novel findings presented, to extract integrated themes, and draw insight from the data. It is clear that genetic factors play a major role in the etiology of mood disorders.